Inositol polyphosphates intersect with signaling and metabolic networks via two distinct mechanisms

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 44; pp. E6757 - E6765
• Main Authors: Wu, Mingxuan, Chong, Lucy S., Perlman, David H., Resnick, Adam C., Fiedler, Dorothea
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01.11.2016
• Series: PNAS Plus
• Subjects: Biological Sciences; Diphosphates - metabolism; Eukaryotes; Eukaryotic Cells - metabolism; Glucose - metabolism; Inositol Phosphates - metabolism; Magnesium; Metabolic Networks and Pathways - physiology; Molecules; Nucleotides - metabolism; Ontology; Phosphorylation; PNAS Plus; Polyphosphates - metabolism; Proteins; Proteome; Ribosomes - metabolism; Saccharomyces cerevisiae - metabolism; Signal transduction; Signal Transduction - physiology; metabolism; affinity reagents; protein pyrophosphorylation; signal transduction; inositol pyrophosphates
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1606853113

Inositol-based signaling molecules are central eukaryotic messengers and include the highly phosphorylated, diffusible inositol polyphosphates (InsPs) and inositol pyrophosphates (PP-InsPs). Despite the essential cellular regulatory functions of InsPs and PP-InsPs (including telomere maintenance, phosphate sensing, cell migration, and insulin secretion), the majority of their protein targets remain unknown. Here, the development of InsP and PP-InsP affinity reagents is described to comprehensively annotate the interactome of these messenger molecules. By using the reagents as bait, >150 putative protein targets were discovered from a eukaryotic cell lysate (Saccharomyces cerevisiae). Gene Ontology analysis of the binding partners revealed a significant overrepresentation of proteins involved in nucleotide metabolism, glucose metabolism, ribosome biogenesis, and phosphorylation-based signal transduction pathways. Notably, we isolated and characterized additional substrates of protein pyrophosphorylation, a unique posttranslational modification mediated by the PP-InsPs. Our findings not only demonstrate that the PP-InsPs provide a central line of communication between signaling and metabolic networks, but also highlight the unusual ability of these molecules to access two distinct modes of action.